In recent years there has been intensive investigations to further the cause of asymmetric reduction specifically as it relates to the development of new pharmaceutical intermediates and bulk drugs. This effort has been spurred by the benefits of single isomer or enantiopure compounds used as pharmaceutical drug agents. Factors such as availability and the overall economics and safety related to the use of new reagents has promoted the idea that an ideal chiral reducing agent could be fabricated from cost effective precursors with the chiral moiety being derived from readily available members of the chiral pool.
Among the techniques for introducing chirality that are available to the industrial chemist, the one that has proven especially useful is asymmetric reduction. Reduction of unsymmetrical ketones to alcohols is among the most useful. This reaction is achieved by the overall addition of hydride ("H--") to one face of the carbonyl group leading preferentially to the formation of one enantiomer.
It is known in the art that several lithium-based chiral reagents have been synthesized via selective substitution of 1-3 hydrogen atoms of lithium aluminum hydride ("LAH") by protic chiral ligands. Early attempts (A. A. Bothner-By, J. Am. Chem. Soc. 73, 846 (1951)) focused on the reaction of LAH with camphor to produce a reagent consisting of LAH complexed with one equivalent of (+)-isoborneol. This reagent was used to reduce prochiral ketones like methyl ethyl ketone or methyl-t-butyl ketone to produce optically active carbinols. These results were later challenged (P. S. Portoghese, J. Org. Chem. 27, 3359 (1962)) by suggesting that the alcohols obtained by Bothner-By were actually achiral and contaminated with small amounts of (+)-borneol. The failure to induce chirality in simple ketones upon reduction with a reagent utilizing LAH and chiral auxiliaries (-)menthol and (+)borneol was later reported (O. Cervinka, Collect. Czech. Chem. Commun. 30, 1684 (1965); O. Cervinka, Collect. Czech. Chem. Commun. 30, 2403 (1965)). Cervinka was able to demonstrate in later papers that the reduction of pyrrolinium salts and ketamines using LAH modified with chiral terpenoids, such as (+)-borneol, (+)-camphor, (-)-menthol and (+)-homopherehyl alcohol, resulted in the corresponding amines having low optical purity, indicating that only partial enantioselectivity had been achieved.
In 1967, monohydroxy sugar derivatives as well as chiral phenylmethyl- and t-butylcarbinols were used as LAH modifiers in the reductions of simple prochiral ketones with only modest success (O. Cervinka et al., Tetrahedron Lett., 1179 (1967)). While (+)-camphor-modified LAH induced chirality in reduction of methyl ethyl ketone, the resulting enantiomeric excess was only 2% (Y. Minoura et al., J. Polym. Sci. Part A-1 6, 2013 (1968)). Other investigators have reported that successful asymmetric reduction of alpha and beta-dialkylamino ketones could be obtained using LAH modified with three equivalents of (-)-menthol in up to 95% enantiomeric excess (R. Andrisano et al., Tetrahedron, 913 (1973); A. S. Angeloni et al., Gazz. Chim. Ital. 107, 421 (1977)). Some of these results have been unable to be reproduced (S. Yamaguchi et al., Bull. Chem. Soc. Jpn. 50, 3033 (1977).
The use of glucose derivatives as LAH modifiers in the reduction of various substrates has also been reported, although with generally low optical yields (S. R. Landor et al., J. Chem. Soc. Chem. Commun., 585 (1966); S. R. Landor et al., J. Chem. Soc. Chem. Commun., 1822 (1966); S. R. Landor et al., J. Chem. Soc. C, 2339 (1971); S. R. Landor et al., J. Chem. Soc. Perkin Trans. 1, 1902 (1974). S. R. Landor et al., J. Chem. Soc. Perkin Trans. 1, p. 605 (1974). Mannitol derivatives which had a C2 axis of symmetry have been used as LAH modifiers, but the values of enantiomeric excess obtained in the resulting products were less than 15% (N. Baggett et al., J. Chem. Soc. Perkin Trans. I, 1123 (1977).
The most efficient chiral auxiliary reported to modify LAH was binaphthol ("BINOL"). Use of BINOL and an achiral auxiliary like ethanol as a ligand for LAH has been reported to result in a reagent that reduces several ketones with high enantiomeric excess (e.e.) (&gt;99%) (R. Noyori et al., J. Am. Chem. Soc. 101, 3129 (1979); R. Noyori et al., J. Am. Chem. Soc. 101, 5843 (1979)). However, commercial interest in binaphthol as a stoichiometric reducing agent has been limited due to its extremely high initial cost, complicated synthesis and difficult recovery from a reduction reaction.
Another report has stated that 1,2-amino alcohols and several diamines have been able to impart some asymmetry to hydride reducing agents (M. Asami, and T. Mukaiyama, Heterocycles 12, 499 (1979)).
To the knowledge of the inventors, prior studies have not demonstrated the utility of inexpensive, readily available chiral auxiliaries in boron or aluminum hydride reducing agents, with or without the use of achiral auxiliaries, to impart significant enantioselectivities when reacted with prochiral ketones.
Thus, there is a need for new chiral hydride reducing agents which can be readily derived from inexpensive sources or easily synthesized, and which are capable of enantioselectively delivering a source of hydride to carbonyl or carbonyl-equivalent bearing chemical entities to afford reduction products in good yield and with high enantioselectivity.